This invention pertains to new medications, namely gels, especially for use on the eye.
Generally, active ingredients for use in the eye are supplied in the form of salves, drops, inserts, or even gels. Each of these forms of administration has its advantages and disadvantages. The form of treatment most pleasant for the eye is still the aqueous drop. In contrast to the other forms mentioned, however, it has the shortest residence time on the eye, which means that the treatment frequency is correspondingly higher and the systemic stress thus greater.
The development of gels which reside for a longer period of time on the surface of the eye has therefore been attracting greater attention. These gels frequently have a salve-like consistency and are therefore packaged in tubes. The handling of tubes for the administration of a drop to the eye has disadvantages in many respects, for which reason physicians and patients prefer eye medications in plastic bottles. So far there is no product which logically combines the advantages of aqueous drops, namely, their compatibility and ease of handling, with the advantage of a prolonged residence time on the eye. Although several patents on gels and gel formulations have appeared, the special requirements associated with the use of a gel on the eye have not yet been worked out in them.
Gels based on the use of carbomer (polymer based on acrylic acid) and mixtures of carbomer with other polymers are known. Especially in connection with uses in the eye, carbomer gels have the property of undergoing a considerable change in consistency after administration. A desirable, water-supplying effect is associated with this property, as a result of which this gel offers advantages, especially in the case of dry eyes. To achieve at the same time a residence time on the eye which is longer than that of pure aqueous drops, however, the concentration of the carbomer must be so high that the gel has a relatively high viscosity and thus can be dispensed only from tubes, which is therefore disadvantageous with respect to administration.
Mixtures of carbomer with other polymers for the production of gels have been developed primarily for dermatological purposes in the form of "adhesive salves" and in the form of "gel plasters" for covering wounds (e.g., U.S. Pat. No. 4,524,064; U.S. Pat. No. 5,013,769; European Patent No. 280,737 Al). Although in these cases a gel must be prepared in a preliminary stage, the goals pursued by the product are quite different, namely, to cover wounds. For this purpose, the product must be nearly insoluble in water and elastic; it is also required to undergo very little shrinkage and to adhere firmly to the skin. In this type of application, the absorption of wound secretions is especially important. The gels in question acquire this property by the incorporation of a large amount of a water-binding agent such as sorbitol, mannitol, etc. A concentration of sorbitol, etc., which is significantly higher than the isotonic concentration is harmful to the eye. Necessarily, therefore, the properties which derive from the formulations claimed in the patents cited above are quite different and in fact tend to be unfavorable for use in the eye, inasmuch as these preparations remove moisture and show poor compatibility because of the high concentrations they contain. Eye inserts are known to exert similar effects.
Another patent (U.S. Pat. No. 4,983,385) pertains to an improvement to the adhesion behavior of fat-containing salves especially with respect to moist body surfaces such as mucous membranes. This problem is solved by the incorporation of carbomer and other water-soluble polymer mixtures into the aqueous phase of the salve.
Another patent (European Patent No. 312,208 Al) describes aqueous gels, but each of these contains only a single polymer. Here, too, none of the special requirements associated with use in the eye (e.g., with respect to compatibility and form of administration) is taken into account.
The known gels do not offer all of the advantages sought for an ophthalmologic gel. It is an object of this invention to provide such gels that can be applied in the form of gels and be dispensed from standard commercial eye drop bottles. The original viscosity of the gel is the key factor which determines drippability. Drippability ensures greater ease of handling, because the product can be dispensed from a standard commercial eye drop bottle. The accuracy with which the contents can be measured is much better from bottles than from tubes, from which a gel usually emerges in the form of a "strand". Suitable original viscosities are in the range of about 10,000-50,000 mPa.s (the viscosity values are based on the measurement with a Brookfield viscometer, as described in the examples).
It is further an object of this invention to provide gels having an adjustable residual viscosity on the eye. A certain residual viscosity develops on the eye as a result of the mixing of the gel with components of the lachrymal film, primarily the inorganic salts. Because of the known properties of carbomers (collapse of the gel structure), this residual viscosity is much lower than the original viscosity as it exists before contact with the lachrymal fluid. The residual viscosity which develops on the eye is the factor which ultimately determines the compatibility and the residence time of the gel on the surface of the eye. Both the duration of the activity and the intensity of the activity of the eye medication are increased by an increase in the residual viscosity. A residual viscosity which is too high, however, leads to adhesive effects, to the feeling of the presence of a foreign body, and thus to compatibility problems. Suitable residual viscosities are in the range of 20-2,000 mPa.s.
It is further an object of this invention to provide gels into which active ingredients and preservatives normally used in ophthalmology may be incorporated. Because precipitations can occur occasionally through interactions between the carboxyl groups of the carbomer and organic bases in particular, there are limits on the amounts of active ingredients and preservatives which can be incorporated into carbomer gels. Most of the active ingredients used in ophthalmology consist of organic bases or their salts. Several important preservatives also belong to this class of compounds.
In arriving at a gel which meets these objectives, the problem was to manage two effects which proceed in opposite directions, namely, the original and the residual viscosities. For a gel to be capable of administration in the form of drops, it is necessary for its original viscosity to be relatively low, which means that it can contain only a relatively small amount gel-forming material. As a rule, this usually means that the residual viscosity after administration to the eye will be rather low. It will be so low, in fact, that hardly any noticeable improvement will be achieved in the residence time of the gel on the eye. If the amount of gel-forming material used (carbomer) is increased to achieve a more suitable (higher) residual viscosity, the result is an original viscosity which in practice no longer allows the product to be dispensed in the form of drops from a bottle. Through the effective addition of salts (inorganic salts, including the salts of organic amines and amino acids) to these gels with a high original viscosity, however, the original viscosity can be reduced to a point at which satisfactory drippability can be achieved.
It was desired to develop a gel formulation which exhibits a defined ratio of original to residual viscosity, the goal being to produce a drippable gel with a prolonged residence time on the surface of the eye. However, since the incorporation of active ingredients and possibly of preservatives must also be taken into account, it turned out to be impossible to accomplish this task simply by discovering a suitable carbomer concentration and then by adding a salt, i.e., by exploiting the known properties of carbomers. On the contrary, it was necessary to discover a new formulation which would be suitable.